Disease relevance of Srebf1

• In conclusion, SREBP-1 regulation of lipogenesis is highly involved in the development of fatty livers but does not seem to be a determinant of obesity in Lep(ob)/Lep(ob) mice [1].
• In contrast, the mRNA abundance of SREBP-1 and lipogenic enzymes in the adipose tissue of Lep(ob)/Lep(ob) mice was profoundly decreased despite sustained fat, which could explain why the SREBP-1 disruption had little effect on obesity [1].
• Constitutively active SREBP-1-overexpressing mice had fatty livers without hepatomegaly, hypoglycemia, or hypertriglyceridemia [2].
• Role of sterol regulatory element-binding protein 1 in regulation of renal lipid metabolism and glomerulosclerosis in diabetes mellitus [3].
• Our study therefore indicates that renal SREBP-1 expression is increased in diabetes and that SREBP-1 plays an important role in the increased lipid synthesis, TG accumulation, mesangial expansion, glomerulosclerosis, and proteinuria by increasing the expression of transforming growth factor beta and vascular endothelial growth factor [3].

High impact information on Srebf1

• However, unlike SREBP itself, PGC-1beta reduces fat accumulation in the liver while greatly increasing circulating triglycerides and cholesterol in VLDL particles [4].
• Further, PGC-1beta is required for SREBP-mediated lipogenic gene expression [4].
• Transcription factors in the sterol responsive element binding protein (SREBP) family are key regulators of the lipogenic genes in the liver [4].
• The transcriptional increase in SREBP-1c mRNA by RXR/LXR was accompanied by a similar increase in the level of the nuclear, active form of the SREBP-1c protein and an increase in fatty acid synthesis [5].
• Expression of the related gene products, SREBP-1a and SREBP-2, were not increased [5].

Chemical compound and disease context of Srebf1

• The role of hyperglycemia in the up-regulation of SREBP-1 was confirmed in renal cells cultured in a high glucose media [3].
• We have previously shown that exposure of C57BL/6J mice to intermittent hypoxia (IH) leads to 1) hypertriglyceridemia due to upregulation of pathways of lipid biosynthesis, including sterol regulatory element binding protein (SREBP)-1 and stearoyl CoA desaturase (SCD)-1; and 2) hypercholesterolemia due to impaired cholesterol uptake [6].
• Moreover, a lower nuclear availability of both SREBP-1 and SREBP-2 mature forms was observed in HepG2 human hepatoblastoma cells treated with arachidonate, EPA or DHA [7].
• These finding suggest that metabolism of ethanol increased hepatic lipogenesis by activating SREBP-1 and that this effect of ethanol may contribute to the development of alcoholic fatty liver [8].
• The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance [9].

Biological context of Srebf1

• Unlike full-length SREBP-1c, the NH2-terminal fragment enters the nucleus without a requirement for proteolytic release from cell membranes, and hence it is immune to downregulation by sterols [10].
• Polyunsaturated fatty acids (PUFAs) are not only ligands for peroxisome proliferator-activated receptor (PPAR) alpha but are also negative regulators of hepatic lipogenesis, which is thought to be mediated by the repression of sterol regulatory element-binding protein (SREBP)-1 [11].
• We evaluated the hypothesis of sterol-regulatory element-binding protein (SREBP)-1c being a general mediator of the transcriptional effects of insulin, with a focus on adipocytes, in which insulin profoundly influences specific gene expression [12].
• Lipid homeostasis is transcriptionally regulated by three DNA-binding proteins, designated sterol regulatory element-binding protein (SREBP)-1a, -1c, and -2 [13].
• SREBP-1a has a longer transcriptional activation domain and is a more potent transcriptional activator than SREBP-1c in cultured cells and liver [14].

Anatomical context of Srebf1

• Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells [10].
• Thus, some of the effects of insulin and/or SREBP-1c in mature fat cells might require C/EBPbeta or C/EBPdelta as transcriptional relays [12].
• In keeping with the regulation by insulin, we show that ACBP is a sterol regulatory element-binding protein 1c (SREBP-1c) target gene in hepatocytes [15].
• In conclusion, activation of LXRbeta in pancreatic beta-cells increases insulin secretion and insulin mRNA expression via SREBP-1-regulated pathway [16].
• Up-regulation of SREBP-1c and lipogenic genes in skeletal muscles after exercise training [17].

Associations of Srebf1 with chemical compounds

• Because this active form of SREBP-1c controls the transcription of genes involved in fatty acid biosynthesis, our results reveal a unique regulatory interplay between cholesterol and fatty acid metabolism [5].
• In this report, we describe a novel LXR target, the sterol regulatory element-binding protein-1c gene (SREBP-1c), which encodes a membrane-bound transcription factor of the basic helix-loop-helix-leucine zipper family [5].
• We have produced transgenic mice whose livers express a dominant positive NH2-terminal fragment of sterol regulatory element binding protein-1c (SREBP-1c) [10].
• We have previously shown that the disruption of SREBP-1 in ob/ob mice decreased their liver triglyceride storage [11].
• The SREBP-1c isoform is a known mediator of insulin action on hepatic gene expression, but its transcriptional effects due to glucose or fructose are still unclear [18].
• We also show similar cooperative activation of the mitochondrial glycerol-3-phosphate acyltransferase promoter by USF and SREBP-1c [19].
• Taken together, these studies reveal that there are alternative molecular mechanisms for activating SREBP target genes in response to the different dietary challenges of Zetia/lovastatin versus fasting/refeeding [20].

Physical interactions of Srebf1

• This region was shown to be responsible for SREBP binding and activation of the ACAS gene by gel shift and luciferase reporter gene assays [21].
• This increased hepatic lipogenesis has been largely attributed to the LXR-dependent up-regulation of sterol regulatory element-binding protein 1c (SREBP-1c) expression [22].
• A 48-h exposure to IFN-gamma also resulted in a decrease of both CCAAT/enhancer-binding alpha and sterol regulatory element binding protein (SREBP-1) expression [23].
• Yin yang 1 protein negatively regulates high-density lipoprotein receptor gene transcription by disrupting binding of sterol regulatory element binding protein to the sterol regulatory element [24].
• Previous promoter analysis revealed that liver X receptor alpha (LXRalpha)/retinoid X receptor alpha (RXRalpha) complex was required for SREBP-1c gene expression in cell culture [25].

Regulatory relationships of Srebf1

• Down-regulation of SREBP-1 expression with the specific small interfering RNA blocked basal and LXRbeta-induced expression of pancreatic duodenal homeobox 1 (PDX-1), insulin, and Glut2 genes [16].
• These results demonstrate that SREBP-2 appears to promote adipocyte differentiation as well as SREBP-1 and that the proteolytic activation of SREBPs may be induced by an as-yet unidentified mechanism in lipid loaded adipocytes [26].
• While the PUFA/cholesterol (PUFA/CH) diets repressed the maturation of the SREBP-1, the SCD1 mRNA levels, and protein and enzyme activity were induced [27].
• A role for PPARalpha in the control of SREBP activity and lipid synthesis in the liver [28].
• The LXR-induced SREBP-1c precursor, however, is rapidly cleaved on acute exposure to insulin via a phosphatidylinositol 3-kinase-dependent mechanism [29].

Other interactions of Srebf1

• A subset of 33 genes met the stringent combinatorial criteria of induction in both SREBP transgenics and decreased expression in SCAP-deficient mice [30].
• In conclusion, PUFAs ameliorate obesity-associated symptoms, such as hepatic steatosis and insulin resistance, presumably through both down-regulation of SREBP-1 and activation of PPARalpha [11].
• The increase in SREBP-1 was associated with increased expression of FAS and acetyl CoA carboxylase, resulting in increased TG content, increased expression of transforming growth factor beta1 and vascular endothelial growth factor, mesangial expansion, glomerulosclerosis, and proteinuria [3].
• Our observations demonstrated that oleate produced by SCD is necessary for fructose-mediated induction of lipogenic gene expression through SREBP-1c-dependent and -independent mechanisms and suggested that SCD1 gene expression is important in lipid and carbohydrate homeostasis [18].
• Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(-/-) mouse liver [31].
• These findings provide in vivo and in vitro evidence that RXR/LXR up-regulates SREBP1c gene expression and that FOXO1 antagonizes this effect of RXR/LXR in skeletal muscle [32].

Analytical, diagnostic and therapeutic context of Srebf1

• Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes [30].
• Here we show by DNA chip microarray analysis that expression of the sterol regulatory element-binding protein (SREBP)-1 gene, a downstream target of insulin, was paradoxically increased in 16-week-old IRS-2(-/-) mouse liver, where insulin-mediated intracellular signaling events were substantially attenuated [31].
• Northern blot analysis of the livers from transgenic mice demonstrated that this gene was highly induced by SREBP-1a, SREBP-1c, and SREBP-2 [21].
• A 2.8-fold increase in SREBP-1 gene expression in CIH was confirmed by real-time PCR (P = 0.001) [33].
• Molecular dissection of the FAS promoter shows that most if not all of this action of ADD1/SREBP1 is through an E-box motif at -64 to -59, contained with a sequence identified previously as the major insulin response element of this gene [34].

References